Targeting regulatory T cell metabolism in disease: Novel therapeutic opportunities

Halvorson, Torin; Tuomela, Karoliina; Levings, Megan K.

doi:10.1002/eji.202250002

Cited by 8 publications

(6 citation statements)

References 126 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…They also inhibit T-cell activation and polarization by expressing granzyme B and CD73. Their metabolic state has been shown to be important for their suppressive function, and its targeting offers new therapeutic opportunities ( 46 ). They utilize a variety of metabolic pathways but take up a considerable amount of glucose ex vivo, and their highly glycolytic metabolism is required for their activation and proliferation ( 47 , 48 ).…”

Section: Discussionmentioning

confidence: 99%

Microenvironmental regulation of T-cells in pulmonary hypertension

Plecitá-Hlavatá,

Brázdová,

Křivonosková

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

IntroductionIn pulmonary hypertension (PH), pulmonary arterial remodeling is often accompanied by perivascular inflammation. The inflammation is characterized by the accumulation of activated macrophages and lymphocytes within the adventitial stroma, which is comprised primarily of fibroblasts. The well-known ability of fibroblasts to secrete interleukins and chemokines has previously been implicated as contributing to this tissue-specific inflammation in PH vessels. We were interested if pulmonary fibroblasts from PH arteries contribute to microenvironmental changes that could activate and polarize T-cells in PH.MethodsWe used single-cell RNA sequencing of intact bovine distal pulmonary arteries (dPAs) from PH and control animals and flow cytometry, mRNA expression analysis, and respirometry analysis of blood-derived bovine/human T-cells exposed to conditioned media obtained from pulmonary fibroblasts of PH/control animals and IPAH/control patients (CM-(h)PH Fibs vs CM-(h)CO Fibs).ResultsSingle-cell RNA sequencing of intact bovine dPAs from PH and control animals revealed a pro-inflammatory phenotype of CD4+ T-cells and simultaneous absence of regulatory T-cells (FoxP3+ Tregs). By exposing T-cells to CM-(h)PH Fibs we stimulated their proinflammatory differentiation documented by increased IFNγ and decreased IL4, IL10, and TGFβ mRNA and protein expression. Interestingly, we demonstrated a reduction in the number of suppressive T-cell subsets, i.e., human/bovine Tregs and bovine γδ T-cells treated with CM-(h)PH-Fibs. We also noted inhibition of anti-inflammatory cytokine expression (IL10, TGFβ, IL4). Pro-inflammatory polarization of bovine T-cells exposed to CM-PH Fibs correlated with metabolic shift to glycolysis and lactate production with increased prooxidant intracellular status as well as increased proliferation of T-cells. To determine whether metabolic reprogramming of PH-Fibs was directly contributing to the effects of PH-Fibs conditioned media on T-cell polarization, we treated PH-Fibs with the HDAC inhibitor SAHA, which was previously shown to normalize metabolic status and examined the effects of the conditioned media. We observed significant suppression of inflammatory polarization associated with decreased T-cell proliferation and recovery of mitochondrial energy metabolism.ConclusionThis study demonstrates how the pulmonary fibroblast-derived microenvironment can activate and differentiate T-cells to trigger local inflammation, which is part of the vascular wall remodeling process in PH.

show abstract

Section: Discussionmentioning

confidence: 99%

Microenvironmental regulation of T-cells in pulmonary hypertension

Plecitá-Hlavatá,

Brázdová,

Křivonosková

et al. 2023

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…However, these cells were also enriched in genes related to the metabolic pathways of glycolysis and oxidative phosphorylation, although still to a lesser extent compared to Tconvs. Both of these pathways have been shown to be necessary for Treg phenotype and function, with more investigation needed to understand how CAR signaling can be modified for optimal metabolic effects 103 . Of note, the metabolic effects of CARs are being extensively explored in Tconvs 104 .…”

Section: S: the Antigen‐specificity Eramentioning

confidence: 99%

“…Both of these pathways have been shown to be necessary for Treg phenotype and function, with more investigation needed to understand how CAR signaling can be modified for optimal metabolic effects. 103 Of note, the metabolic effects of CARs are being extensively explored in Tconvs. 104 For example, CARs encoding 4-1BB promote a memory phenotype characterized by low glycolysis and high mitochondrial oxidative phosphorylation, enabling long-term survival in vivo.…”

Section: Car Tregsmentioning

confidence: 99%

Eras of designer Tregs: Harnessing synthetic biology for immune suppression

Tuomela

Salim

Levings

2023

Immunological Reviews

Self Cite

View full text Add to dashboard Cite

SummarySince their discovery, CD4+CD25hiFOXP3hi regulatory T cells (Tregs) have been firmly established as a critical cell type for regulating immune homeostasis through a plethora of mechanisms. Due to their immunoregulatory power, delivery of polyclonal Tregs has been explored as a therapy to dampen inflammation in the settings of transplantation and autoimmunity. Evidence shows that Treg therapy is safe and well‐tolerated, but efficacy remains undefined and could be limited by poor persistence in vivo and lack of antigen specificity. With the advent of new genetic engineering tools, it is now possible to create bespoke “designer” Tregs that not only overcome possible limitations of polyclonal Tregs but also introduce new features. Here, we review the development of designer Tregs through the perspective of three ‘eras’: (1) the era of FOXP3 engineering, in which breakthroughs in the biological understanding of this transcription factor enabled the conversion of conventional T cells to Tregs; (2) the antigen‐specificity era, in which transgenic T‐cell receptors and chimeric antigen receptors were introduced to create more potent and directed Treg therapies; and (3) the current era, which is harnessing advanced genome‐editing techniques to introduce and refine existing and new engineering approaches. The year 2022 marked the entry of “designer” Tregs into the clinic, with exciting potential for application and efficacy in a wide variety of immune‐mediated diseases.

show abstract

“…An increasing body of evidence points to the metabolic state of the TME as a critical factor favoring Treg survival and function. The availability of factors such as fatty acids, glucose, and oxygen within the TME have all been shown to promote Treg differentiation, function, expansion, or survival [3]. In particular, the presence of lactic acid is emerging as one of the most significant properties of the TME that favors Tregs.…”

mentioning

confidence: 99%

“…The mechanism by which an acidic pH promotes Treg induction remains unclear. A low pH has been shown to inhibit glycolysis in conventional T cells [15], and reduced glycolysis has been linked to increased Treg induction [3]. However, Rao et al did not observe any clear impairment in glycolysis after culture in lactic acid [14].…”

mentioning

confidence: 99%

Acidity promotes the differentiation of immunosuppressive regulatory T cells

Tuomela

Levings

2023

Eur J Immunol

View full text Add to dashboard Cite

The metabolic milieu is emerging as a major contributing factor in the maintenance of the immunosuppressive microenvironment within tumors. In particular, the presence of lactic acid produced by highly glycolytic cancer cells is known to suppress antitumor immune cell subsets while promoting immunosuppressive cell populations, such as regulatory T cells (Tregs). Unlike conventional T cells, Tregs have a unique, potent ability to take up lactic acid to fuel both mitochondrial metabolism and gluconeogenesis, thus supporting suppressive function and proliferation. In this issue of the European Journal of Immunology [Eur. J. Immunol. 2023.53:2250258], Rao et al. uncover a novel mechanism by which lactic acid can support Treg accumulation within tumors in mice. This study shows that lactic acid, through a pH-dependent mechanism rather than lactate itself, promotes TGFβinduced differentiation of Tregs from conventional CD4 + T cells. These findings build on the already multifaceted role of lactic acid in maintaining an immunosuppressive tumor microenvironment. Keywords: lactic acid r regulatory T cells r Treg metabolism r immunosuppressive microenvironment See accompanying article by Rao et al. Regulatory T cells (Tregs) contribute to maintaining the immunosuppressive tumor microenvironment (TME) through a combination of mechanisms, including anti-inflammatory cytokine production, down-modulation of costimulatory molecules on antigen-presenting cells, and direct killing of cytotoxic T cells [1, 2]. A high proportion of Tregs within the TME correlates with poor prognosis across a range of solid tumors [1], underscoring the need to therapeutically target these cells. However, what drives the preferential accumulation and function of Tregs in the TME compared to antitumor effector immune cell subsets remains an

show abstract

Targeting regulatory T cell metabolism in disease: Novel therapeutic opportunities

Cited by 8 publications

References 126 publications

Microenvironmental regulation of T-cells in pulmonary hypertension

Microenvironmental regulation of T-cells in pulmonary hypertension

Eras of designer Tregs: Harnessing synthetic biology for immune suppression

Acidity promotes the differentiation of immunosuppressive regulatory T cells

Contact Info

Product

Resources

About